Complementary and alternative medicines(CAMs) are widely used for treatment of inflammatory diseases. A subset of these CAMs include microbial products, protobiotics, and live and killed bacteria. Recent work using a Salmonella-based CAM that expresses colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli can treat experimental autoimmune encephalomyelitis (EAE). Mode of action by the Salmonella-CFA/I CAM is attributed to its ability to suppress innate inflammatory responses, as well by immune deviation to promote T helper (Th) cell 2 bias. Similar protective therapeutic intervention was also obtained with just the Salmonella vector, but efficacy was not as potent as that obtained using the Salmonella-CFA/I. Subsequent analysis revealed that oral dosing with either Salmonella CAM could induce regulatory CD25+ CD4+ T (Treg) cells, and the difference in protection was attributed to the potency of the induce Treg cells. These findings led us to speculate that the Salmonella-CFA/I CAM possesses anti-inflammatory properties that may be applicable to treating arthritis. Thus, the hypothesis to be tested in this application is that oral administration with Salmonella CAMs, specificially, Salmonella-CFA/I, will reduce disease severity and limit disease progression in an experimental rheumatoid arthritis (RA) model. The widely used type II collagen-induced arthritis (CIA) murine model for RA will be tested using DBA/1 and C57BL/6 mice. To test this hypothesis, two Specific Aims are proposed. Studies in Specific Aim 1 will determine the effectiveness of Salmonella CAMs treatment upon CIA. Studies in Specific Aim 2 will determine which regulatory T cell subset is responsible for protection against CIA and determine which inflammatory Teff cell subset is diminished. These studies will provide the basis for future development of strategies to regulate RA. This application is responsive to RFA-AT-06-005: "Mechanisms of Immune Modulation" by addressing the requested research areas in understanding CAMs' mechanisms of action upon the induction and expansion of T cell regulatory populations. [unreadable] [unreadable] [unreadable]